Polyphenols from hickory nut reduce the occurrence of atherosclerosis in mice by improving intestinal microbiota and inhibiting trimethylamine N-oxide production.

BACKGROUND: Trimethylamine N-oxide (TMAO), a metabolite produced by intestinal microbiota through metabolizing phosphatidylcholine, choline, l-carnitine and betaine in the diet, has been implicated in the pathogenesis of atherosclerosis (AS). Concurrently, dietary polyphenols have garnered attention for their potential to ameliorate obesity, diabetes and atherosclerosis primarily by modulating the intestinal microbial structure. Hickory (Carya cathayensis) nut, a polyphenol-rich food product favored for its palatability, emerges as a candidate for exploration. HYPOTHESIS/PURPOSE: The relationship between polyphenol of hickory nut and atherosclerosis prevention will be firstly clarified, providing theoretical basis for the discovery of natural products counteracting TMAO-induced AS process in hickory nut. STUDY DESIGN AND METHODS: Employing Enzyme-linked Immunosorbent Assay (ELISA) and histological examination of aortic samples, the effects of total polyphenol extract on obesity index, inflammatory index and pathological changes of atherosclerosis in C57BL/6 J mice fed with high-fat and high choline diet were evaluated. Further, the composition, abundance, and function of mouse gut microbiota were analyzed through 16srDNA sequencing. Concurrently, the levels of TMAO and the expression of key enzymes (CutC and FMO3) involved in its synthesis are quantified using ELISA, Western Blot and Real-Time Quantitative PCR (RT-qPCR). Additionally, targeted metabolomic profiling of the hickory nut polyphenol extract was conducted, accompanied by molecular docking simulations to predict interactions between candidate polyphenols and the CutC/FMO3 using Autodock Vina. Finally, the docking prediction were verified by microscale thermophoresis (MST) . RESULTS: Polyphenol extracts of hickory nut improved the index of obesity and inflammation, and alleviated the pathological changes of atherosclerosis in C57BL/6 J mice fed with high-fat and high-choline diet. Meanwhile, these polyphenol extracts also changed the composition and function of intestinal microbiota, and increased the abundance of microorganisms in mice. Notably, the abundance of intestinal microbiota endowed with CutC gene was significantly reduced, coherent with expression of CutC catalyzing TMA production. Moreover, polyphenol extracts also decreased the expression of FMO3 in the liver, contributing to the reduction of TMAO levels in serum. Furthermore, metabonomic profile analysis of these polyphenol extracts identified 647 kinds of polyphenols. Molecular docking predication further demonstrated that Casuariin and Cinnamtannin B2 had the most potential inhibition on the enzymatic activities of CutC or FMO3, respectively. Notably, MST analysis corroborated the potential for direct interaction between CutC enzyme and available polyphenols such as Corilagin, (-)-Gallocatechin gallate and Epigallocatechin gallate. CONCLUSION: Hickory polyphenol extract can mitigate HFD-induced AS by regulating intestinal microflora in murine models. In addition, TMA-FMO3-TMAO pathway may play a key role in this process. This research unveils, for the inaugural time, the complex interaction between hickory nut-derived polyphenols and gut microbial, providing novel insights into the role of dietary polyphenols in AS prevention.

N-carbamylglutamate supplementation induces functional egg production in layers by modulating liver transcriptome profiles.

Eggs rich in polyunsaturated fatty acids (PUFA), known as functional eggs, are animal products deemed beneficial to human health and possess high economic value. The production of functional eggs involves supplementing exogenous additives with the ability to regulate lipid metabolism. As N-Carbamylglutamate (NCG) serves as an endogenous arginine synthesizer, and arginine acts as the substrate for the formation of nitric oxide (NO), the biological function of NCG is partially mediated by NO. NO is a key regulatory molecule in lipid metabolism, suggesting that NCG may also have the ability to modulate lipid metabolism. In order to assess the capacity of NCG in regulating liver lipid metabolism and its potential application in producing functional eggs, we conducted a study to investigate the effects of dietary supplementation of NCG on production performance, serum, and liver NO levels, yolk fatty acid composition, and the liver transcriptome of layers. In this study, we utilized 30 layers of the Jinghong No.1 breed, all aged 45 wk. All the birds were randomly divided into 2 groups. Each group had 5 replicates, and each replicate had 3 birds. We provided them with different diets: one group received the basic diet, and the other group's diet was supplemented with 0.08% NCG. The experiment lasted for 14 wk. The results did not reveal any positive impact of NCG on production performance. However, NCG supplementation elevated NO levels in serum and liver, along with an increase in yolk PUFA, ω-3, and ω-6 fatty acids. Liver transcriptome analysis identified 124 upregulated differentially expressed genes (DEGs) and 43 downregulated DEGs due to NCG supplementation. Functional annotation using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database highlighted 3 upregulated DEGs (CPT1A, MOGAT1, and CHKA) and 2 downregulated DEGs (FASN and ETNPPL) associated with lipid metabolism. Pathway enrichment analysis revealed that CPT1A was enriched in the AMPK signaling pathway and the PPAR signaling pathway, while FASN was enriched in the AMPK signaling pathway. Thus, CPT1A and FASN are potential functional genes related to lipid metabolism facilitated by NCG supplementation. In summary, our study suggests that NCG supplementation modulates liver lipid metabolism, leading to the production of functional eggs in layers.

Effects of transcutaneous electrical acupoint stimulation (TEAS) on postoperative pain in patients undergoing gastric and esophageal ESD surgery: a study protocol for a prospective randomized controlled trial.

BACKGROUND: Post-operative pain of endoscopic submucosal dissection (ESD) is always be overlooked and undertreated by endoscopists. However, the incidence of moderate to severe pain after ESD is as high as 44.9% to 62.8%, which can greatly affect the patient's recovery, reduce their satisfaction, and extend their hospital stay. Transcutaneous electrical acupoint stimulation (TEAS) have been shown to reduce postoperative pain and enhance gastrointestinal (GI) function recovery in patients undergoing abdomen surgery. However, there is no evidence regarding on the effect of TEAS on post-operative pain and complications in patients undergoing ESD. Therefore, we aim to investigate whether perioperative TEAS treatment is superior to the sham acupuncture in terms of post-ESD pain and GI function recovery. METHODS: This study is a prospective, randomized controlled trail, which is single-blinded and in single center. A total of 120 patients undergoing elective gastric and esophageal ESD surgery in Beijing Friendship Hospital, Capital Medical University, will be involved in this study. These individuals will be stratified according to the type of ESD surgery (i.e. gastric or esophageal procedure) and be randomly divided into two groups. L14, PC6, ST36 and ST37 will be stimulated at the TEAS treatment group, and the control group will receive simulation at four sham acupoints. The primary outcome is post-EDS VAS score at the time of entering PACU, 10 min, 20 min, 30 min, 1 h, 2 h, 4 h, 6 h, 18 h, 24 h, 48 h after the surgery. The secondary outcomes include the anesthesia-associated parameters, sedation score, nausea and vomiting score, shivering score, recovery of gastrointestinal function, satisfaction of patients to anesthesia, incidence of postoperative complications, QLQ-C30 life quality scale, and the economic indicators. DISCUSSION: The results of this study will confirm that continuous preventive application of TEAS can alleviate the postoperative pain among patients with gastric and esophageal ESD surgery and accelerate the recovery of post-ESD gastrointestinal function. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ID: ChiCTR2100052837, registered on November 6, 2021. http://www.chictr.org.cn/showproj.aspx?proj=135892 .

Endophytic fungus Colletotrichum sp. AP12 promotes growth physiology and andrographolide biosynthesis in Andrographis paniculata (Burm. f.) Nees.

Endophytic fungi can promote host plant growth, enhance antioxidant defense enzyme activity, and induce the biosynthesis and accumulation of secondarymetabolites. Therefore, using endophytic fungi to improve the quality and yield of medicinal plants or important crops is an effective means of regulation. Colletotrichum sp. AP12 has been reported to produce andrographolide compounds (ADCs). This study aimed to investigate the effects of AP12 and its elicitors on the growth, defense enzyme activity, accumulation, and transcription levels of key genes in Andrographis paniculata (Burm. f.) Nees (A. paniculata). Using fermentation method to prepare AP12 into the inactivated fermentation solution (IFS), fermentation solution (FS), inactivated mycelium solution (IMS), and mycelium solution (MS), and the results showed that all four fungal elicitor components (ECs) could promote A. paniculata growth, enhance antioxidant defense enzymes, and increase ADC content and yield, especially the IMS group that had the highest leaf area, whole plant dry weight, superoxide dismutase (SOD), catalase (CAT) enzyme activities, total lactone contents, and yields, which were 2.37-, 1.60-, 2.20-, 3.27-, 1.59-, and 2.65-fold of the control, respectively. The 14-deoxyandrographolide (NAD) in the host irrigated with MS was 3.35-fold that of the control. In addition, AP12-infected A. paniculata sterile seedlings could significantly increase ADC content and expression levels of key enzyme genes, especially on day 12, when the total lactone content of the host reached 88.881± 5.793 mg/g DW, while on day 6, CPS gene expression level reached 10.79-fold that of the control, in turn promoting the biosynthesis and accumulation of andrographolide. In conclusion, the endophytic fungus AP12 is beneficial to the growth and secondary metabolism of A. paniculata, which is helpful for the cultivation and application of the biological bacterial fertilizer in A. paniculata, providing a theoretical and research basis for the use of endophytic fungi as a microbial resource to improve the quality and yield of medicinal plants.

Facile and green fabrication of tumor- and mitochondria-targeted AIEgen-protein nanoparticles for imaging-guided photodynamic cancer therapy.

In recent years, aggregation-induced emission (AIE)-active materials have been emerging as a promising means for bioimaging and phototherapy. However, the majority of AIE luminogens (AIEgens) need to be encapsulated into versatile nanocomposites to improve their biocompatibility and tumor targeting. Herein, we prepared a tumor- and mitochondria-targeted protein nanocage by the fusion of human H-chain ferritin (HFtn) with a tumor homing and penetrating peptide LinTT1 using genetic engineering technology. The LinTT1-HFtn could serve as a nanocarrier to encapsulate AIEgens via a simple pH-driven disassembly/reassembly process, thereby fabricating the dual-targeting AIEgen-protein nanoparticles (NPs). The as designed NPs exhibited an improved hepatoblastoma-homing property and tumor penetrating ability, which is favorable for tumor-targeted fluorescence imaging. The NPs also presented a mitochondria-targeting ability, and efficiently generated reactive oxygen species (ROS) upon visible light irradiation, making them valuable for inducing efficient mitochondrial dysfunction and intrinsic apoptosis in cancer cells. In vivo experiments demonstrated that the NPs could provide the accurate tumor imaging and dramatic tumor growth inhibition with minimal side effects. Taken together, this study presents a facile and green approach for fabrication of tumor- and mitochondria-targeted AIEgen-protein NPs, which can serve as a promising strategy for imaging-guided photodynamic cancer therapy. STATEMENT OF SIGNIFICANCE: AIE luminogens (AIEgens) show strong fluorescence and enhanced ROS generation in the aggregate state, which would facilitate the image-guided photodynamic therapy [12-14]. However, the major obstacles that hinder biological applications are their lack of hydrophilicity and selective targeting [15]. To address this issue, this study presents a facile and green approach for the fabrication of tumor­ and mitochondria­targeted AIEgen-protein nanoparticles via a simple disassembly/reassembly of the LinTT1 peptide-functionalized ferritin nanocage without any harmful chemicals or chemical modification. The targeting peptide-functionalized nanocage not only restricts the intramolecular motion of AIEgens leading to enhanced fluorescence and ROS production, but also confers good targeting to AIEgens.

[Comparison of alkaloids in Aconiti Kusnezoffii Radix, Aconiti Radix, and Aconiti Lateralis Radix Praeparata based on UHPLC-Q-Exactive Orbitrap MS/MS].

UHPLC-Q-Exactive Orbitrap MS/MS was used to systematically analyze and compare the alkaloids in Aconiti Kusnezoffii Radix, Aconiti Radix, and Aconiti Lateralis Radix Praeparata. After the samples were pretreated in the solid-phase extraction cartridges, 0.1% ammonium hydroxide(A)-acetonitrile(B) was used for gradient elution. The LC-MS method for characterization of alkaloids in the three herbal medicines was established in ESI positive ion mode to collect high resolution MS data of reference substances and samples. On the basis of the information of reference substance cracking behavior, retention time, accurate molecular mass, and related literature, a total of 155 alkaloids were identified in Aconiti Kusnezoffii Radix, Aconiti Radix, and Aconiti Lateralis Radix Prae-parata. Specifically, 130, 127, and 92 alkaloids were identified in Aconiti Kusnezoffii Radix, Aconiti Radix, and Aconiti Lateralis Radix Praeparata, respectively. Monoester alkaloids and amino-alcohol alkaloids were dominant in the three herbal medicines, and the alkaloids in Aconiti Kusnezoffii Radix and Aconiti Radix were similar. This paper can provide a reference for elucidating the pharmacological effects and clinical application differences of the three herbal medicines produced from plants of Aconitum.

Application of Data Fusion in Traditional Chinese Medicine: A Review.

Traditional Chinese medicine is characterized by numerous chemical constituents, complex components, and unpredictable interactions among constituents. Therefore, a single analytical technique is usually unable to obtain comprehensive chemical information. Data fusion is an information processing technology that can improve the accuracy of test results by fusing data from multiple devices, which has a broad application prospect by utilizing chemometrics methods, adopting low-level, mid-level, and high-level data fusion techniques, and establishing final classification or prediction models. This paper summarizes the current status of the application of data fusion strategies based on spectroscopy, mass spectrometry, chromatography, and sensor technologies in traditional Chinese medicine (TCM) in light of the latest research progress of data fusion technology at home and abroad. It also gives an outlook on the development of data fusion technology in TCM analysis to provide references for the research and development of TCM.

Toxicity of zearalenone and its nutritional intervention by natural products.

Zearalenone (ZEN) is a toxic secondary metabolite mainly produced by fungi of the genus Fusarium, and is often present in various food and feed ingredients such as corn and wheat. The structure of ZEN is similar to that of natural estrogen, and it can bind to estrogen receptors and has estrogenic activity. Therefore, it can cause endocrine-disrupting effects and promote the proliferation of estrogen receptor-positive cell lines. In addition, ZEN can cause oxidative damage, endoplasmic reticulum stress, apoptosis, and other hazards, resulting in systemic toxic effects, including reproductive toxicity, hepatotoxicity, and immunotoxicity. In the past few decades, researchers have tried many ways to remove ZEN from food and feed, but it is still a challenge to eliminate it. In recent years, natural compounds have become of interest for their excellent protective effects on human health from food contaminants. Researchers have discovered that natural compounds often used as dietary supplements can effectively alleviate ZEN-induced systemic toxic effects. Most of the compounds mitigate ZEN-induced toxicity through antioxidant effects. In this article, the contamination of food and feed by ZEN and the various toxic effects and mechanisms of ZEN are reviewed, as well as the mitigation effects of natural compounds on ZEN-induced toxicity.

Expression of Mir-489-3p as an Effective Marker of Poor Prognosis in Patients with Non-small-cell Lung Carcinoma.

Context: Lung carcinoma accounts for the majority of cancer deaths, and its 5-year survival rate isn't optimistic. Remarkable progress has been made in recent decades toward understanding the biological behavior of non-small-cell lung carcinoma (NSCLC) and creating targeted molecular therapies for diagnosis and treatment. However, little literature is available on the topic, and the clinical significance and application of miR-489-3p for NSCLC can't yet be determined. Objective: The study intended to determine if miR-489-3p can predict prognosis for patients with NSCLC. Design: The research team designed a prospective study to examine in depth and analyze the molecular science of NSCLC tumors in a clinical setting. Setting: The study took place in the Department of the Special Ward at the Shanxi Provincial Cancer Hospital in Taiyuan, Shanxi, China. Participants: Participants were 116 patients with NSCLC at the hospital and 87 healthy people. Outcome Measures: A type of microRNA (miRNA), MiR-489-3p, was detected using nano-polymerase chain reaction (PCR). The diagnostic value of miR-489-3p for lung carcinoma and its predictive value for death from the disease were analyzed using a receiver operating characteristic (ROC) curve, and the three-year prognosis for patients was examined. Human NSCLC cell lines and normal, human, lung epithelial cells were obtained, and miR-489-3p was detected to assess the biological effects on lung-cancer cells. Results: MiR-489-3p has low expression in lung-cancer tissues, which indicates its good predictive value for prognosis for and death of lung-cancer patients. The activity of tumor cells increased after the inhibition of miR-489-3p. Conclusions: A low level of miR-489-3p indicates a poor prognosis for patients with NSCLC. A deeper understanding of the mechanism of miR-489-3p in lung carcinoma may be the key to the earlier diagnosis and treatment of lung carcinoma.

A New Source of Diterpene Lactones From Andrographis paniculata (Burm. f.) Nees-Two Endophytic Fungi of Colletotrichum sp. With Antibacterial and Antioxidant Activities.

Endophytic fungi of medicinal plants are abundant, and their metabolites often have antioxidant, antibacterial, and antitumor effects and can produce secondary metabolites identical or similar to those of their hosts, which can mitigate the problem of insufficient supply of medicinal plants. In this study, we screened endophytic fungi for strains that produce the same diterpene lactones as Andrographis paniculata based on their biological activity. Firstly, the dominant group of endophytic fungi of Andrographis paniculata was screened and pathogenicity was studied using Koch's rule. Secondly, DPPH, ABTS, OH, PTIO radical scavenging, and FRAP assays were used to detect the antioxidant activity of the extracellular extracts of the strains, and total phenol and total flavonoid contents of the strains with high antioxidant capacity were determined. S. aureus, B. subtilis, E. coli, and P. aeruginosa were used to determine the antibacterial activity of the mycelial extracts of the strains. Finally, the secondary metabolites of the mycelial extracts of the strains were examined by high-performance liquid chromatography. The results showed that 32 strains of Andrographis paniculata were relatively isolated > 70% and non-pathogenic. Extracellular extracts of strains AP-1 and AP-4 showed vigorous antioxidant activity, and AP-4, AP-12, AP-47, and AP-48 showed antibacterial activity against four strains of bacteria. The HPLC results indicated that the mycelial extracts of AP-4 and AP-12 contained diterpene lactones. The two endophytic fungi were recognized as Colletotrichum sp. The study successfully obtained diterpene lactones from the endophytic fungus of Andrographis paniculata and confirmed the feasibility of using endophytic fungal strains to produce active substances consistent with the host. It was also useful for exploring endophytic fungi and medicinal plants. The relationship provides theoretical guidance.

Successfully treated recalcitrant atopic eczema with acupoint autohemotherapy: A case report and hypothesized mechanism of the therapy.

Acupoint autohemotherapy at bilateral Zusanli (ST36) and Xuehai (SP10) was used to treat a 26-year-old female patient who had suffered from recalcitrant atopic eczema (AE) for five years. The treatment was applied at a frequency of once per week for the first month, followed by a three-month period of once every other week. At the end of treatment, the patient's AE symptoms were entirely resolved, and by the end of a six-month follow-up her immunoglobulin E level had returned to the normal range. Further, there was no relapse of AE symptoms during the six-month follow-up. Therefore, we hypothesized that after the repeated treatments the local inflammatory reaction induced by autologous blood injection triggered a local immune response, followed by a systemic immune response after the repeated treatment, finally leading to the anti-inflammation and immunomodulation effects. This case suggests that acupoint autohemotherapy could be used as an effective complementary treatment for recalcitrant AE, especially in cases where other treatments have failed. Further comparative studies are needed to corroborate the value and mechanisms of this therapy.

Glutamine relieves the hypermetabolic response and reduces organ damage in severe burn patients: A multicenter, randomized controlled clinical trial.

BACKGROUND: Severe burns can cause a hypermetabolic response and organ damage. Glutamine is a conditionally essential amino acid with various pharmacological effects. In this study, whether glutamine could alleviate the hypermetabolic response and maintain organ function after burn injury was analyzed. METHODS: A multicenter, randomized, single-blind, parallel controlled trial was conducted to evaluate the efficacy of glutamine in decreasing hypermetabolism after burn injury. Physiological and biochemical indexes, such as vital signs, metabolic hormones, metabolic rate, and organ damage, were recorded on the 7th and 14th days after treatment. RESULTS: In total, 55 adult burn patients with a total burn surface area (TBSA) of 30-70% were included in this study and randomly divided into the burn control (B, 28 patients) and burn+glutamine (B+G, 27 patients) groups. Except for the glutamine administration, the groups did not differ in the other treatments and nutrition supplements. The levels of diamine oxidase (DAO), lactulose/mannitol (L/M), ß2-microglobulin, lactate dehydrogenase (LDH), hydroxybutyrate dehydrogenase (HBD) and cardiac troponin l (cTnl) in the B+G group were significantly lower than those in the B group (p < 0.05 or 0.01). The levels of resting energy expenditure (REE), serum catecholamines, glucagon, lactate and Homeostasis model assessment (HOMA) in the B+G group were significantly lower than those in the B group (p < 0.05 or 0.01). No significant difference was found in the length of hospitalization or the mortality rate between the two groups (p > 0.05). CONCLUSIONS: Glutamine moderately alleviates the hypermetabolic response and reduces organ damage after severe burns. Therefore, the early application of glutamine, which is effective and safe, should be used as an active intervention as early as possible.

Genome sequence and transcriptome of Sorbus pohuashanensis provide insights into population evolution and leaf sunburn response.

Sorbus pohuashanensis (Hance) Hedl. is a potential horticulture and medicinal plant, but its genomic and genetic backgrounds remain unknown. Here, we sequence and assemble the S. pohuashanensis reference genome using PacBio long reads. Based on the new reference genome, we resequence a core collection of 22 Sorbus spp. samples, which are divided into 2 groups (G1 and G2) based on phylogenetic and PCA analyses. These phylogenetic clusters are highly consistent with their classification based on leaf shape. Natural hybridization between the G1 and G2 groups is evidenced by a sample (R21) with a highly heterozygous genotype. Nucleotide diversity (π) analysis shows that G1 has a higher diversity than G2 and that G2 originated from G1. During the evolution process, the gene families involved in photosynthesis pathways expanded and the gene families involved in energy consumption contracted. RNA-seq data suggests that flavonoid biosynthesis and heat-shock protein (HSP)-heat-shock factor (HSF) pathways play important roles in protection against sunburn. This study provides new insights into the evolution of Sorbus spp. genomes. In addition, the genomic resources, and the identified genetic variations, especially those related to stress resistance, will help future efforts to produce and breed Sorbus spp.

Interpretation of updated NCCN guidelines for non-small cell lung cancer (version 1, 2022) / 中国胸心血管外科临床杂志

@#The National Comprehensive Cancer Network (NCCN) has updated and released the latest content of the NCCN guidelines for the clinical diagnosis and treatment of non-small cell lung cancer (NSCLC) in the version 1, 2022. Based on high-quality clinical evidence and the latest research progress of the diagnosis and treatment of NSCLC, the guidelines have been widely recognized and welcomed by clinicians around the world. Compared with the version 7, 2021, the new version has been updated and revised in some parts of chapters and sections, mainly focusing on targeted therapies and molecular testing. This article will interpret the updated therapy content of the new version.

Angelica sinensis polysaccharide (ASP) attenuates diosbulbin-B (DB)-induced hepatotoxicity through activating the MEK/ERK pathway.

Diosbulbin-B (DB) is a promising therapeutic drug for cancer treatment; however, DB-induced hepatotoxicity seriously limits its clinical utilization. Based on this, the present study investigated whether the Angelica sinensis extract, angelica sinensis polysaccharide (ASP), was effective to attenuate DB-induced cytotoxicity in hepatocytes. The primary hepatocytes were isolated from rats and cultured in vitro, which were subsequently treated with high-dose DB (100 µM) and ASP (12 µg/ml) to establish the DB-induced hepatotoxicity models. MTT assay and flow cytometry (FCM) were performed to evaluate cell viability, and the results showed that high-dose DB-induced cell apoptosis and inhibition of proliferation were reversed by co-treating cells with ASP, which were supported by our Western Blot assay data that ASP upregulated Cyclin D1 and CDK2 to abrogate high-dose DB-induced cell cycle arrest. In addition, ASP exerted its regulating effects on cell autophagy, and we found that ASP increased LC3B-II/I ratio and Atg5, but decreased p62 to activate the autophagy flux. Of note, the MEK/ERK pathway could be activated by ASP in the DB-treated hepatocytes, and the protective effects of ASP on high-dose DB-induced hepatocyte death were abolished by co-treating cells with the autophagy inhibitor (3-methyladenine, 3-MA) and MEK/ERK selective inhibitor (SCH772984). Moreover, blockage of the MEK/ERK pathway suppressed cell autophagy in the hepatocytes co-treated with ASP and high-dose DB. Taken together, this in vitro study illustrated that ASP activated the MEK/ERK pathway mediated autophagy to suppress high-dose DB-induced hepatotoxicity.

Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a serious global public health threat. The 3C-like protease (3CLpro) is a virus protease encoded by SARS-CoV-2, which is essential for virus replication. We have previously reported a series of small-molecule 3CLpro inhibitors effective for inhibiting replication of human coronaviruses including SARS-CoV-2 in cell culture and in animal models. Here we generated a series of deuterated variants of a 3CLpro inhibitor, GC376, and evaluated the antiviral effect against SARS-CoV-2. The deuterated GC376 displayed potent inhibitory activity against SARS-CoV-2 in the enzyme- and the cell-based assays. The K18-hACE2 mice develop mild to lethal infection commensurate with SARS-CoV-2 challenge doses and were proposed as a model for efficacy testing of antiviral agents. We treated lethally infected mice with a deuterated derivative of GC376. Treatment of K18-hACE2 mice at 24 h postinfection with a derivative (compound 2) resulted in increased survival of mice compared to vehicle-treated mice. Lung virus titers were decreased, and histopathological changes were ameliorated in compound 2-treated mice compared to vehicle-treated mice. Structural investigation using high-resolution crystallography illuminated binding interactions of 3CLpro of SARS-CoV-2 and SARS-CoV with deuterated variants of GC376. Taken together, deuterated GC376 variants have excellent potential as antiviral agents against SARS-CoV-2.

Effect of Xingbi Gel Nasal Drops on Fyn-STAT5 Pathway in Nasal Mucosa Fibroblasts of Guinea Pigs with Allergic Rhinitis.

Fyn-STAT5 is considered to be the frontier signaling pathway of IgE-mediated allergic reactions related to mast cell activation, but research on allergic rhinitis (AR) has been rarely reported. Xingbi gel nasal drops (XGND) are a compound preparation of traditional Chinese medicine, which has the exact therapeutic efficacy on AR. The current study aimed to observe the effects of XGND on Fyn-STAT5 pathway in AR guinea pig nasal mucosal fibroblasts in vitro and further illuminate the possible therapeutic mechanism of XGND on AR. The isolated and cultured nasal mucosa fibroblasts from AR guinea pigs were identified by immunocytochemical staining. Real-time PCR and western blot were performed to detect the mRNA and protein levels of the Fyn-STAT5 pathway and related cytokines in AR guinea pig nasal mucosal fibroblasts. The results indicated that XGND may interfere with the Fyn-STAT5 pathway by reducing the expression of Fyn and SCF and upregulating STAT5 and IL-10, thereby inhibiting proliferation and degranulation of mast cells, correcting Th1/Th2 immune imbalance, and then alleviating the immune response of AR fibroblasts. Our study revealed the possible regulatory mechanism of XGND in AR and laid an experimental foundation for improving the clinical efficacy of AR and enriching the clinical medication for AR.

College of American Pathologists Tumor Regression Grading System for Long-Term Outcome in Patients with Locally Advanced Rectal Cancer.

BACKGROUND: The National Comprehensive Cancer Network's Rectal Cancer Guideline Panel recommends American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) system to evaluate pathologic response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC). Yet, the clinical significance of the AJCC/CAP TRG system has not been fully defined. MATERIALS AND METHODS: This was a multicenter, retrospectively recruited, and prospectively maintained cohort study. Patients with LARC from one institution formed the discovery set, and cases from external independent institutions formed a validation set to verify the findings from discovery set. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed by Kaplan-Meier analysis, log-rank test, and Cox regression model. RESULTS: The discovery set (940 cases) found, and the validation set (2,156 cases) further confirmed, that inferior AJCC/CAP TRG categories were closely /ccorrelated with unfavorable survival (OS, DFS, LRFS, and DMFS) and higher risk of disease progression (death, accumulative relapse, local recurrence, and distant metastasis) (all p < .05). Significantly, pairwise comparison revealed that any two of four TRG categories had the distinguished survival and risk of disease progression. After propensity score matching, AJCC/CAP TRG0 category (pathological complete response) patients treated with or without adjuvant chemotherapy displayed similar survival of OS, DFS, LRFS, and DMFS (all p > .05). For AJCC/CAP TRG1-3 cases, adjuvant chemotherapy treatment significantly improved 3-year OS (90.2% vs. 84.6%, p < .001). Multivariate analysis demonstrated the AJCC/CAP TRG system was an independent prognostic surrogate. CONCLUSION: AJCC/CAP TRG system, an accurate prognostic surrogate, appears ideal for further strategizing adjuvant chemotherapy for LARC. IMPLICATIONS FOR PRACTICE: The National Comprehensive Cancer Network recommends the American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) four-category system to evaluate the pathologic response to neoadjuvant treatment for patients with locally advanced rectal cancer; however, the clinical significance of the AJCC/CAP TRG system has not yet been clearly addressed. This study found, for the first time, that any two of four AJCC/CAP TRG categories had the distinguished long-term survival outcome. Importantly, adjuvant chemotherapy may improve the 3-year overall survival for AJCC/CAP TRG1-3 category patients but not for AJCC/CAP TRG0 category patients. Thus, AJCC/CAP TRG system, an accurate surrogate of long-term survival outcome, is useful in guiding adjuvant chemotherapy management for rectal cancer.

[Changes in Algal Particles and Their Water Quality Effects in the Outflow River of Taihu Lake].

Connected rivers are a common engineering method to ensure the ecological health of urban water. However, for the lakes with serious cyanobacteria blooms, the algal particles are carried by the outflow of the lake and will have a significant impact on water quality. The location at which the Liangxi river meets Meiliang Bay of Lake Taihu was selected to explore the influence of the eutrophic lake on the connected rivers, and high-frequency monitoring was conducted in summer for three consecutive years to analyze the changes in the flux of cyanobacterial bloom particles in rivers and their impact on river water quality. The results show that:① The improvement of the algal cyanobacteria bloom in Meiliang Bay and the operation of the pressure-controlled algae well at the entrance of the river significantly reduced the concentration of chlorophyll a and the flux of algae particles in the Liangxi River. The average value of the concentration of chlorophyll a and the flux of algae particles in the river in summer 2019 were 54.34 µg·L-1 and 84.7 t·d-1, respectively, and significantly lower than those of 2017; ② Water diversion had a significant effect on improving the water quality of the receiving water. Except for DTP, the nitrogen and phosphorus concentrations of the remaining forms of the Liangxi River showed a downward trend from 2017 to 2019, indicating that the water quality of the Liangxi river improved after water transfer; ③ A large amount of cyanobacterial blooms entering the channel significantly increased the particulate nitrogen and phosphorus content of the water. From 2017 to 2019, the nitrogen and phosphorus in the Liangxi River were mainly PN and PP, accounting for 62.5% and 70.8% of TN and TP, respectively; ④ The water quality of the Beijing-Hangzhou Grand Canal and other connected rivers has not been affected by the algal particles in Meiliang Bay. In August 2019, the chlorophyll a content in the canal water decreased by 65% compared with that of June, indicating that cyanobacterial bloom particles have not accumulated in the Grand Canal; ⑤ On the premise that the cyanobacteria bloom in the lake has not been effectively improved, the algae particles carried by the water diversion will have an impact on the water quality and landscape of the local reach connecting the river.

Interpretation of updated NCCN guidelines for small cell lung cancer (version 1. 2022) / 中国胸心血管外科临床杂志

@#The National Comprehensive Cancer Network (NCCN) released the latest version 1, 2022 of "NCCN guidelines for the clinical diagnosis and treatment of small cell lung cancer" (hereinafter referred to as "guideline"). Based on high-quality evidence-based medicine, this guideline provides references of clinical diagnosis and treatment for clinicians around the world. Compared with the version 3, 2021 of the "guideline", updates and revisions mainly focused on the progress of radiotherapy and systemic treatment. This article will interpret the updated therapy content in this new version of the "guideline".